1. Field of Endeavor
The present invention relates to devices, systems, and processes useful to treat Restless Leg Syndrome.
2. Brief Description of the Related Art
In 1685 Thomas Willis, an 17th century English physician, published the first description of what we now term “restless legs syndrome” (“RLS”).(1,2) He characterized patients with this disorder as, “Wherefore to some, when being a bed they betake themselves to sleep, presently in the Arms and Legs Leapings and Contractions of the Tendons, and so great a Restlessness and Tossing of their Members ensure, that the diseased are no more able to sleep, than if they were in a Place of greatest Torture.” In 1945, Karl Axel Ekbom coined the term “restless legs syndrome” and suggested a neurological instead of a psychiatric origin to the disorder.(3) Ekbom focused attention on the abnormal sensory component of the disease.
With development of “Sleep Labs” in the 1970's, the sleep-robbing nature of RLS was objectively characterized.(4) In 1990 the American Sleep Disorders Association defined RLS as (i) disagreeable touch sensations seemingly originating in the legs, that (ii) come upon some nights and not other nights, and that (iii) are relieved almost immediately upon standing or walking. In 1999, a task force of the American Academy of Sleep Medicine summarized the then current understanding of RLS.(5) Diagnostic criteria were further expanded in 1995 and 2004 by international groups to include episodes occurring during the daytime when drowsy.(6,7)
Disagreeable touch sensations were cataloged as “creepy-crawly, ants crawling, jittery, pulling, worms moving, soda bubbles in veins, electric shock, pain, the gotta moves, burning, jimmy legs, hebbie jeebies, tearing, throbbing, tight feeling, grabbing, Elvis legs, itching bones, crazy legs, and fidgets.”(7) With symptom descriptions as bizarre as these, it is no wonder that early investigators lumped patients with RLS in with patients with psychiatric hysterical (conversion) disorders. However, clinical responses to various categories of (8) drugs and to iron therapy and the presence of at least two genetically identifiable phenotypes all argue in favor of a physical and not a psychological origin to RLS.(9)
RLS is a common disorder: prevalence of symptoms 5 or more nights per month were reported in 3% of individuals 18-29 years, 10% in 30-79 years, and 19% in those 80 or older.(10) Age adjusted prevalence in this study was 10%. In a similar study, prevalence was 11.5% with half of those reporting RLS symptoms causing moderate to very severe discomfort.(11) Others have described a rise in prevalence with age but have set peak prevalence at 70-79 years with a slight drop off in people 80 years and older.(12) Whatever the peak prevalence of RLS, it is more common in older individuals than younger and it severely affects emotional well-being in the elderly.(13,14)
A study of 23,000 individuals conducted in France, Germany, Spain, and the UK concluded that 11.1% of the general population have RLS and that in 50% of patients RLS symptoms significantly disrupted everyday activities and personal relationships.(15) A companion study of over 15,000 individuals determined that 5% of the population had RLS attacks at least twice weekly.(16) RLS is now sufficiently common that in the 2007 issue of Time Magazine it was featured in “The Year in Medicine from A to Z”.(17) Although quite common, RLS is not commonly recognized by primary-care physicians even when a diagnostic description is given by the patient to his doctor.(18) However, when primary-care physicians are made aware of RLS, they can identify RLS in a high proportion of patients.(19,20)
RLS can be early in onset (before the age of 45) with slow progression of symptoms and run in families, or it can come on later in life, involving one member of a family with rapid development of severe symptoms.(12,21-24)
Because RLS is common, it has been observed in association with a wide variety of other disorders and diseases. Some have interpreted these associations as causal links. Such causal interpretations need to be viewed with great caution. The list includes metabolic and hormonal abnormalities, pregnancy, peripheral neuropathies, spinal and brainstem lesions, decreased serum magnesium and folate levels, anemia, rheumatoid arthritis, amyloidosis, carcinoma, musculoskeletal disease, anxiety, depression, multiple sclerosis, cognitive defects, hypertension, blood donors, heart disease, reduced libido, social isolation, gastroesophageal reflux, migraine headache, chronic lung disease, caffeine use, varicose veins, sleep apnea, gastric surgery, drug withdrawal, hypothyroidism, acute intermittent porphyria, arborizing telangiectasia, cholesterol microemboli, diabetes, periodic limb movement disorder in sleep (PLMS), somatoform pain disorder, being Caucasian, and more.(2,25-40,40-45)
However, by 2007, only two published studies of patients selected from the general population accurately measured the association of RLS with other disorders.(46,47) These two studies found that diabetes, reduced renal function, and anemia are significantly associated but make only a small contribution to the overall prevalence of RLS. Even in the older age groups where the RLS is most prevalent, secondary disorders and diseases increase RLS prevalence by only 10-20%.
Unlike these two general population studies, many small associative studies have identified patients with specific disorders or diseases and then compared RLS prevalence in these selected populations with the general population or with controls. In a review of 16 publications focused on patients with end-stage renal disease on dialysis published between 1991-2005, 15 (93.8%) of the 16 studies demonstrated higher prevalence rates in these dialysis patients than in the general population.(36) In one study, 84% of patients with end-stage renal disease had RLS. To support this association, it has been observed that in some patients, symptoms of RLS dramatically decrease following renal transplantation.(48) Like RLS in others, in dialysis patients RLS leads to poor sleep and thereby to a low quality of life.(49) Patients with RLS suffer from daytime sleepiness, depression, poor concentration, and even fear of long-distance travel during which their legs may become restless while awake.(9)
In a publication examining RLS and pregnancy, four studies demonstrated prevalence rates higher than the general population, while one showed rates no different that those observed in the general population.(36) Others have reported an association of RLS with pregnancy.(50) This association is further supported by the observation that the frequency of RLS attacks drops dramatically following childbirth.(51,52) Goodman et al. present a very convincing reverse “S” shaped-curve showing a dramatic decrease in RLS episodes following delivery.(53) In another study of pregnant women, an association was observed between RLS and parity.(47) Women who had given birth to three or more children had a three times greater risk of having RLS compared to nulliparous women or to men.
Iron deficiency has been associated with RLS since 1945, although the connection between the two disorders is not clear-cut.(3,36,54) Correction of peripheral anemia does not always decrease RLS symptoms. Furthermore, most patients with RLS are not anemic. When studied by magnetic resonance imaging, iron abnormalities associated with RLS were observed in the substantia nigra of the brainstem.(55) Decreased serum ferritin (below 50 ng/mL) and cerebral spinal fluid ferritin levels have been associated with RLS.(2) Patients with RLS appear to have a decreased ability to transport iron into the central nervous system through the blood brain barrier.(56)
A wide variety of peripheral neuropathies have been connected with RLS including cryoglobulinemia, Charcot-Marie-Tooth ataxia type 2, diabetic, and amyloid types.(57-60)
To prospectively evaluate the concomitant occurrence of RLS and varicose veins in a population seeking treatment for varicose veins, and to assess the therapeutic response of RLS to sclerotherapy, 1397 patients with varicose veins were screened for RLS symptoms by questionnaire and interview. RLS symptoms were present in 312 (22%) of the 1,397 patients. Sclerotherapy with sodium tetradecyl sulphate was performed on 113 RLS patients. 111 (98.2%) of 113 treated patients reported initial relief from RLS symptoms. Follow-up showed recurrence rates of 8% and 28% at 1 and 2 years, respectively.(61)
And finally, RLS has been associated with the phenomenon of periodic leg movements in sleep (PLMS).(30) In 1953, Symonds described an involuntary clonic-like movement of the lower extremities that occurred during sleep, often waking the patient over and over again at night.(62) In 1965, Lugaresi et al. documented the presence of PLMS in patients with RLS.(63) In a polysomnographic study of 133 individuals with RLS, Montplaisir et al. observed PLMS in 80.2% of these individuals using a one-night's sleep PLMS index score of greater than 5 (one of the many definition of abnormal PLMS).(64) However, PLMS has also been observed in association with other forms of insomnia such as narcolepsy, rapid-eye-movement sleep disorder, and obstructive sleep apnea.(7) It has also been observed in normals.(7) Because RLMS is associated with many diseases and disorders and with normals, patients with RLS comprise only a fraction of patients with PLMS. At best the diagnosis of RLMS is “supportive” of the diagnosis of RLM; it is not diagnostic.
If RLS is caused by one of these associated disorder or disease, and if correction of the associated disorder or disease can stop the symptoms of RLS, then treatment is straight forward: treat the associated disorder or disease. Except for pregnancy and some forms of anemia, these associative disorders or diseases are not generally amenable to treatment. For most of these patients, palliation of RLS symptoms is the only treatment available.
On the other hand, in the vast majority of patients suffering from RLS, there is no associated disorder or diseases of the legs.(26) That is, in most individuals, RLS is idiopathic or primary in nature.(65) Their affected limbs are no different than limbs of people without RLS. Skin, muscles, bones, nerves, arterial or venous circulation, spinal reflexes, electromyography, nerve conduction studies, and imaging examination are all normal in patients with primary RLS.(12,52)
In patients with primary RLS, the anatomic site of origin of RLS appears to be in the central nervous system above the level of the spinal cord and below the level of the cerebral cortex.(12) The site of origin may be at the subcortical level, perhaps at the level of the thalamus and cerebellum.(66)
FIG. 1 includes an illustration showing a leg and the major classes of somatic sensory receptors, highly specialized cells associated with neurons that convert various forms of energy from physical stimuli into nerve impulses. The hairy skin H (including free nerve endings, nociceptors, Merkel's disks, and Ruffini's corpuscles), periosteum and interosseous membrane P (including Pacinian corpuscles), the gastrocnemius muscle, muscles M including muscle spindles, glabrous skin G (including free nerve endings, nociceptors, Merkel's disks, and Ruffini's corpuscles, and Meissner's corpuscles), joints J (including joint receptors), tendons and ligaments T (including Ruffini's corpuscles and Golgi tendon organs), and subcutaneous tissue S (including Pacinian corpuscles) are illustrated (67).
Whether secondary or primary, central to RLS is the nighttime onset of disagreeable somatic sensations that appear to originate in a leg or in legs. Of our five senses, touch is the most heterogeneous in character. Touch encompasses the sensation of pain and temperature, pressure and crude touch, fine or discriminatory touch, and vibratory sensation. A variety of specialized microscopic receptors or mechanical-electrical transducers are present in skin, subcutaneous tissues, muscles, tendons and ligaments, joints, and periosteum and interosseous membranes to distinguish different types of touch sensations, as shown in FIG. 1. These specialized transducers or filters include Pacinian corpuscles which are encapsulated, onion-like nerve coverings that sense deep pressure and vibrations in the 250-350 Hz range; Meissner's corpuscles which are oval structures surrounding nerve and located between dermal papillae and which detect pressure and low frequency vibration in the 30-50 Hz range; Merkel's discs which are spherical collection of cells that identify static pressure and respond to low frequency vibrations in the 5-15 HZ range; Ruffini's corpuscles which are elongated structures in the dermis that detect skin stretching and the sense of slipping; Golgi tendon organs, joint receptors, and muscle spindles that identify stretching, and free nerve endings that sense temperature and pain.(67)
Three distinct somatic sensory neuronal pathways exist for the legs. Each pathway begins in the leg and ends with a neuronal signals reaching the cerebral cortex and, hence, consciousness.
Pathway No. 1: When painful stimuli or changes in temperature excite the leg, they cause sensory nerves in skin to fire. These primary neurons then synapse in the ipsilateral dorsal horn of the spine with secondary neurons of the contralateral lateral spinothalamic tract. These lateral spinothalamic nerves then course up the spine reaching the thalamus on the opposite side of the stimulus. In the thalamus, these axons synapse with tertiary neurons that exit the thalamus and ascent in the internal capsule and terminate in the postcentral or sensory gyrus of the cerebral cortex.
Pathway No. 2: Pressure and crude touch nerves follow a similar pathway with the addition of fibers from the primary neuron for several spinal segments in the ipsilateral dorsal white matter column.
Pathway No. 3: Neurons that transmit the senses of fine or discriminatory touch, proprioception, and vibratory touch follow a different pathway to the thalamus. For the legs, the primary sensory neurons ascend in the ipsilateral fasciculus gracilis of the dorsal column of the spine to the ipsilateral nucleus gracilis in the medulla. In the nucleus gracilis these primary neurons synapse with secondary neurons which then cross the midline to ascend in the contralateral medial lemniscus to the thalamus. Tertiary neurons then ascend to the postcentral or sensory cortex, just as with other touch sensations. Since this wide variety of somatic leg sensation all reach the thalamus, it makes sense that the unpleasant leg sensations in patients with RLS are very diverse in character.
For patients with primary or secondary RLS, the terribly unpleasant touch sensations of RLS that often start during sleep are mapped to their leg or legs (and, much less commonly, to their arm or arms). Since most patients are not actually being subjected to bizarre touch sensations in the affected extremity, the sensations are, in effect, somatic hallucinations. That is, these sensations are perceived to originate in a limb in which no corresponding stimulus is present. For example, at the time some patients with RLS report that a leg feels as though worms are crawling in it, no worms are actually present to explain the sensations experienced. The phantom limb syndrome in amputees is a similar phenomena, where somatic sensations in the brain are mapped by the individual to a limb that is not present. They are not usually referred to as “hallucinations,” but they are.
A partial explanation for the hallucinations that begin during periods of sleepiness and drowsiness or during sleep in patients with RLS may be found in the neuronal circuit that exists between the thalamus and the sensory cortex, referred to as the “thalamocortical loop.”(67) Only two stable membrane potential states exist for thalamocortical neurons. During wakefulness, these neurons fire tonically which allows them to transmit information from peripheral somatic stimuli to the cortex or conscious brain (see Pathways 1-3 above). During sleep, and perhaps during times of sleepiness or drowsiness, the thalamocortical neurons enter an oscillatory state, become synchronized with the cortex, and disconnect the cortex from the outside world. When disconnected, the conscious brain gets its peripheral somatic sensory input not from peripheral somatic sensory neurons but from the thalamus and its varied inputs. The somatosensory brain is no longer looking at the external world; it is focused internally.
The primacy of sensory abnormalities in RLS—as opposed to movement abnormalities—was emphasized in a recent study published by pulmonary physicians (as opposed to sleep physicians) who noted that “The endorsement of twitching or frequent body movements in the current study was so frequent as to render it a nonspecific finding. We cannot draw any conclusions based on this reported symptom in this study, other than to suggest that asking about body twitching may not be useful in the clinical evaluation of patients.”(37) The same authors noted that a consistent diagnosis of RLS could be obtained using a definition of RLS that requires “ . . . uncomfortable leg sensations a few nights a week or more that are worse at night.” Abnormal brain somatosensory processing in RLS patients has been described.(68)
Prior to waking, the unpleasant sensations of RLS lead to leg movements seemingly as an unconscious attempt to diminish the amplitude of the disturbing sensations. Dysfunctional leg movements and their antecedent unpleasant sensations wake the patient who then seeks relief by doing something, commonly getting out of bed and standing or walking. However, even though standing and walking diminish unpleasant limb sensations, they do so at the expense of sleep. Over half of patients with RLS report waking with symptoms 3 or more times per night on nights they experience attacks.(15) Loss of sleep is the ultimate price paid by the patients who suffer from RLS. RLS patients with severe symptoms have the least amount of sleep of any sleep disorder with the exception of sleep-loss associated with mania.(66) The sleep-loss of RLS leads to a generalized decrease in quality of life similar to other forms of insomnia, such as sleep apnea.(15,69) RLS victims are more likely than normals to be late to work, miss work, make errors at work, and miss social events because of sleepiness.(37)
Two drugs are currently labeled by the Food and Drug Administration for the treatment of RLS: Mirapex® (pramipexole dihydrochloride), a nonergot dopamine agonist, and Requip® (ropinirole hydrochloride), a nonergot dopamine agonist. Both agents have a higher binding affinity with D3 dopamine receptor subtypes than for D2 for D4 receptors. In two separate blinded studies of ropinirole, very large placebo affects were observed, suggesting that just the process of focusing attention on patients with RLS helps them considerably.(70,71) Off-label drug prescription for RLS is widespread. Many drugs, including iron preparations, benzodiazepines, opiates, and anticonvulsants have been used to treat RLS.(8) Some dopaminergic agents, such as the combination of levodopa/carbidopa, have caused long-term side effects which include worsening or augmentation of RLS symptoms.(9) Drugs that influence the central nervous system commonly effect more than one region of the brain, making drugs less than desirable as a first line of treatment for RLS. McCrink et al. studied 16,202 individuals, 7% of which had RLS. They documented that health-related quality of life was actually diminished in RLS patients who used prescription medications to treat RLS symptoms.(72)
As previously noted, if correction of a patient's secondary disorder or disease can correct RLS, that disorder or disease should be treated. However, most patients with RLS have no secondary disease or disorder to correct or the secondary disorder or disease is not treatable.
To relieve the unpleasant tactile sensations of RLS, patients resort to all sorts of movements and stimulations of the legs including “ . . . walking about, stomping the feet, rubbing, squeezing or stroking the legs; taking hot showers or baths; or applying ointment, hot packs, or wraps to the legs.”(73) As stated by Jones and Derodra, “The relief of symptoms produced by movement or rubbing may be due to the afferent sensory input effect.”(25) Patients are spontaneously applying an overwhelming or swamping sensory input to serve as a “counterstimulation” to the unpleasant sensations of RLS. Once up and doing something, RLS symptoms usually subside. However, the process of getting up and walking interrupts sleep. And interrupted sleep, over the long haul, leads to decreased wakeful functioning and diminished quality-of-life.
A simple device that could provide a pleasant sensation to overwhelm or swamp the unpleasant sensations of RLS, without fully waking the patient, might be a more desirable first line treatment of RLS than drugs. Counterstimulation is a known medical therapy. To treat auditory hallucinations, personal stereo music has been applied as a counterstimulation to overwhelm or swamp auditory hallucinations.(74) Similarly, to treat a wide variety of chronic pain syndromes, transcutaneous electrical nerve stimulation has been applied as a counterstimulation to overwhelm or swamp pain.(75)
If a counterstimulus could be applied to a RLS patient at the onset of an attack while the patient were in bed, and the counterstimulus could be applied with minimal waking of the patient, sleep efficiency might be improved. As shown by FIG. 2, which illustrates a flow chart showing grades of severity of RLS and types of treatments based upon severity, adapted from Chaudhuri, many patients with mild forms for RLS spontaneously apply a counterstimuli of one sort or another to allow themselves to go back to sleep.(9)
If the RLS patient's self-treatment proves ineffective or if it requires a degree of wakefulness incompatible with a good night's sleep, then a device that applied a counterstimulus without robbing sleep might be useful.
FIG. 3 illustrates a cooling pad, embodying principles of the present invention, applied to a leg, the cooling pad applying no additional pressure than the patient sheet and mattress pad. In some patients, therapeutic counterstimulation could be as simple as making a region of the patients bedding cool, as shown in FIG. 3. Cooling that does not drop to lower than 17° C. is sensed by free nerve fibers as a cool sensation and not pain. Below 17° C., the sensation is identified by other free nerve fibers as pain.(67) (Similarly, above 42° C., heat is no longer sensed as warmth, but as pain.) If the cooling could be turned on at the onset of RLS symptoms and set to turn off as the patient fell back to sleep, a counterstimulation of a single nerve pathway might be sufficient to overwhelm the central sensations of RLS.
FIG. 4 illustrates a hard rubber ball, embodying principles of the present invention, being pressed against a patient's leg such that the skin, subcutaneous tissue, muscle, periosteum, and joints are all effected by the stimulus. In another patient, therapeutic counterstimulation might require the recruitment of a host of somatic sensory nerves to overcome the unpleasant sensations of RLS. FIG. 4 shows a ball pressed against the back of a patients leg with just enough force not to elicit pain. Free nerve endings, Merkel's disks, and Ruffini's corpuscles from the skin, Pacinian corpuscles from subcutaneous tissue, muscle spindles from the muscle, joint receptors from the knee and ankle, and Pacinian corpuscles from the interosseous membrane joining the tibia and the fibula, could all send somatic sensory signals to the brain from this stimulus. If pressure from a ball, or the like, could be applied at the onset of RLS symptoms and removed as the patient fell back to sleep, a counterstimulation from a host nerve pathways might sufficient to overwhelm the unpleasant central sensations of RLS.
A commercially available boot which diffusely applies pressure to the foot and calf has been disclosed on the world wide web (club-cleo.com/cleo-active-leggings-reflexology.html) and offered as a means of treating RLS. Similarly, a boot-like device capable of moving leg fluids to prevent deep vein thrombosis is revealed by Morgenlander in U.S. Published Patent Application Nos. 2003/0176822 A1, US 2005/0026912 A1, and US 2006/0287621 A1, in which the affected limb is subjected to “ . . . positive pressure to an extremity” to effect treatment. Additionally, in U.S. Pat. No. 4,149,529, Copeland discloses an apparatus capable of applying pressure to a leg similar to Morgenlander.